Adenosine is a naturally occurring purine nucleoside that is ubiquitous in mammalian cell types. Adenosine exerts its biological effects by interacting with A1, A2 (further subclassified as A2A and A2B) and A3 cell surface receptors, which modulate important physiological processes.
The A1 and A2A receptor subtypes are believed to play complementary roles in adenosine's regulation of a cell's energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and locally activates the A1 receptor to decrease the oxygen demand or activates the A2A receptor to increase the oxygen supply, thereby reinstating the balance of energy supply and demand within the tissue. The combined action of A1 and A2 subtypes increases the amount of available oxygen to tissue and protects cells against damage caused by a short-term imbalance of oxygen. One of the important functions of endogenous adenosine is to prevent tissue damage during traumas such as hypoxia, an ischemic condition, hypotension and seizure activity.
In addition, modulation of A1 receptors slows conduction velocity in the heart's atrioventricular node, resulting in the normalization of supraventricular tachycardias and control of ventricular rate during atrial fibrillation and flutter. Modulation of A2A receptors also regulates coronary vasodilation.
Adenosine is also a neuromodulator, which modulates molecular mechanisms underlying many aspects of physiological brain function by mediating central inhibitory effects. An increase in neurotransmitter release follows traumas such as hypoxia, ischemia and seizures. Neurotransmitters are ultimately responsible for neural degeneration and neural death, which can cause brain damage or death. Adenosine is thought to be an endogenous anticonvulsant agent that inhibits glutamate release from excitory neurons and neuronal firing. Adenosine agonists, therefore, are useful as antiepileptic agents.
Adenosine plays an important role as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischemia and hypoxia and protect cardiac tissue during and after trauma (preconditioning). Adenosine agonists thus are useful as cardioprotective agents.
The preparation and use of a number of adenosine A1 receptor agonists have been described (Moos et al., J. Med. Chem. 28:1383-1384 (1985); Thompson et al., J. Med. Chem. 34:3388-3390 (1991); Vittori et al., J. Med. Chem. 43:250-260 (2000); Roelen et al., J. Med. Chem., 39:1463-1471 (1996); van der Wenden et al., J. Med. Chem. 41102-108 (1998); Dalpiaz et al., Pharm. Res. 18:531-536 (2001), Beakers et al., J. Med. Chem. 46, 1492-1503 (2003); U.S. Pat. No. 5,589,467 to Lau et al.; U.S. Pat. No. 5,789,416, to Lum et al.; and C. E. Muller, Current Medicinal Chemistry 2000, 7, 1269-1288).
Nucleoside 5′-nitrate esters are reported in Lichtenthaler et al., Synthesis, 199-201 (1974), and U.S. Pat. No. 3,832,341 to Duchinsky et al.
The citation of any reference in Section 2 of this application is not an admission that the reference is prior art to this application.